Nucleoside flexibility

A growing number of coenzyme analogs have been prepared containing modifications in the nicotinamide sugar moiety. These modifications focus on three primary interactions inductive effects, tolerance of sugar substituents (anomeric configuration), and nucleoside flexibility (the importance of an intact furanose... 

Copper(I) tends towards a tetrahedral coordination geometry in complexes. With 2,2 -bipyr-idine as a chelate ligand a distorted tetrahedral coordination with almost orthogonal ligands results. 2,2 -Bipyridine oligomers with flexible 6,6 -links therefore form double helices with two 2,2 -bipyridine units per copper(I) ion (J. M. Lehn, 1987,1988). J. M. Lehn (1990 U. Koert, 1990) has also prepared such helicates with nucleosides, e.g., thymidine, covalently attached to suitable spacers to obtain water-soluble double helix complexes, so-called inverted DNA , with internal positive charges and external nucleic bases. Cooperative effects lead preferentially to two identical strands in these helicates when copper(I) ions are added to a mixture of two different homooligomers. 

However, the nucleoside analogue 164 was found to be devoid of activity against HSV-1, HSV-2, VZV and the cytomegalovirus (CMV) in human fibroblast (MRC-5) cells. In this case the decreased conformational flexibility resulting from the introduction of the cyclopropyl group into 164 appeared to be unfavourable for interaction with the enzymes involved (vide supra. Sect. 2.9) [222]. Likewise, the cyclopropylpyrimidine 166c-f and 167, the cyclopropyl-purine nucleosides 168 showed no antiviral activity against HSV-1, HSV-2, HCMV and HIV-1 in cell culture, Eq. (66) [223]. 

A. Vandemeulebroucke, S. de Vos, E. Van Holsbeke, J. Steyaert, and W. Versees, A flexible loop as a functional element in the catalytic mechanism of nucleoside hydrolase from Trypanosoma vivax, J. Biol. Chem., 283 (2008) 22272-22282. 

To a first approximation, the chiral discrimination should be independent of the nucleophile. The palladium-catalyzed desymmetrization protocol utilizing a heterocyclic nucleophile provides enantio- and diastereoselective entries to diverse carbo-nucleosides. As shown in Scheme 8E.9, introduction of purine bases rather than the hydroxymethyl synthon also affords high enantioselectivities [61]. A variety of natural and unnatural nucleosides can be flexibly prepared because the simple change of ligand chirality or, alternatively, switching the alkylation sequence leads to opposite enantiomers. The palladium-catalyzed approach sharply contrasts with the chiral-pool method, whose enantiodivergency is limited by the availability of the starting material. 

Extensive work has been reported on the chemistry of polyphosphates, in particular that of dinucleoside and sugar nucleoside pyrophosphates. This reflects the reliability and flexibility of the phosphoramidate methods which have been developed over the past few years. Similarly, a wide range of oligonucleotide building blocks, incorporating extensive structural modifications when compared to the natural nucleoside structures, have been described. 

Arabino oligonucleotides up to a hexamer have been prepared by solid phase synthesis using (118) as the monomer the phosphoramidites (118) could be obtained rather pure without 2 -OH protection due to steric hindrance for phosphity-lation at this position. Deoxyoligonucleotides containing flexible nucleoside analogues have been synthesized using (119) or (120) as the modified monomers in both cases hybridization was greatly impeded. 

Oligodeoxyrlbonucleotide analogues containing flexible aliphatic, non-ionic, achiral spacers are of interest as potential anti-sense agents. Analogues containing the 3 0-5 C oxyacetamide linkage were first reported in 1974, and an improved procedure for their preparation has recently been published. The pyridinium salts of 5 -azido-3 -0-carboxymethyl nucleosides... 

There are many examples of 2H lineshape analyses in the review period, but one of particular interest is the work by Drobny et al.37 This study examines the conformational flexibility of the furanose ring, which is of particular importance in the functioning of DNA. They examined the nucleoside [2 -2H]-2 -deoxycytidine deuterated at the C3 position (Fig. 26(a)) and contained in the sequence [d(CGCGAATTCGCG)]2. The furanose ring... 

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